Clinical Question

Evidence-Based Answer

For patients with type 2 diabetes, regular insulin and short-acting insulin analogues are equally effective in the treatment of diabetes and in lowering A1C levels. For patients with type 1 diabetes, short-acting analogues produce a slightly greater reduction of A1C levels than regular insulin. Regular insulin and short-acting insulin cause hypoglycemia at similar rates. No studies have compared the effects of regular insulin and insulin analogues on the long-term complications of diabetes.1

Practice Pointers

Six to 7 million people use insulin or insulin analogues2 in the United States. Patients with type 2 diabetes who maintain tight glucose control have fewer microvascular complications.3 There are many options for the management of insulin in patients with type 1 or type 2 diabetes mellitus. Insulin therapy consists of prandial (bolus) insulin, basal insulin, and correction-dose insulin.4 There are four main types of insulin used for glycemic control: immediate-acting, rapid-acting, intermediate-acting, and long-acting (see accompanying table). Immediate- and rapid-acting insulins are used as bolus insulins; intermediate- and long-acting insulins are used as basal insulins.

Traditional methods of insulin therapy use neutral protamine Hagedorn (NPH) and regular insulin in combination at a ratio of 70:30 taken before morning and evening meals. NPH often is moved to bedtime with regular insulin still taken before the evening meal.2 Another option is prandial insulin with meals in addition to basal insulin once or twice per day. Insulin pumps commonly are used to give continuous subcutaneous insulin.2 One of the benefits of the newer short-acting analogues is their fast onset, which allows patients to take insulin immediately before eating instead of 30 minutes in advance. Also, they enable patients to dose insulin after eating, if needed.1 Disadvantages of short-acting insulin are the high cost and potential long-term side effects. Short-acting insulins are approximately double the cost of regular insulin.2 There also is some concern about the potential mitogenic effects of analogues, and more information is needed on the long-term safety and side effects of these drugs.1

Cochrane Abstract

Background. In short-acting insulin analogues the dissociation of hexamers is facilitated, achieving peak plasma concentrations about twice as high and within approximately one half the time compared with regular human insulin. According to these properties, this profile resembles the shape of patients without diabetes more than that of regular human insulins. Despite this theoretical superiority of short-acting insulin analogues over regular human insulin, the risk-benefit ratio of short-acting insulin analogues in the treatment of patients with diabetes is still unclear.

Search Strategy. A highly sensitive search for randomized controlled trials combined with key terms for identifying studies of short-acting insulin analogues versus regular human insulin was performed using the Cochrane Library (issue 4, 2003), MEDLINE, and EMBASE. Date of last search was December 2003.

Selection Criteria. The authors1 included randomized controlled trials with diabetic patients of all ages that compared short-acting insulin analogues with regular human insulin. Intervention duration had to be at least four weeks.

Data Collection and Analysis. Trial selection as well as evaluation of study quality was done by two independent reviewers. The quality of reporting of each trial was assessed according to a modification of the quality criteria as specified by Schulz (JAMA 1995;273:408–12) and Jadad (Controlled Clin Trials 1996;17:1–12).

Primary Results. Altogether 7,933 participants took part in 42 randomized controlled studies. Most studies were of poor methodological quality. In patients with type 1 diabetes, the weighted mean difference (WMD) of A1C was −0.1 percent (95% confidence interval [CI], −0.2 to −0.1) in favor of insulin analogue, whereas in patients with type 2 diabetes the WMD was estimated to be 0.0 percent (95% CI, −0.1 to 0.1). In subgroup analyses of different types of interventions in patients with type 1 diabetes, the WMD in A1C was −0.2 percent (95% CI, −0.3 to −0.1) in favor of insulin analogue in studies using continuous subcutaneous insulin injections (CSII), whereas for conventional intensified insulin therapy (IIT) studies the WMD in A1C was −0.1 percent (95% CI, −0.2 to 0.0). The WMD of the overall mean hypoglycemic episodes per patient per month was −0.2 percent (95% CI, −1.2 to 0.9) and −0.2 (95% CI, −0.5 to 0.1) for analogues in comparison with regular insulin in patients with type 1 and type 2 diabetes, respectively. For studies in patients with type 1 diabetes, the incidence of severe hypoglycemia ranged from zero to 247.3 (median 20.3) episodes per 100 person-years for insulin analogues and from zero to 544 (median 37.2) for regular insulin. In patients with type 2 diabetes, the incidence ranged from zero to 30.3 (median 0.6) episodes per 100 person-years for insulin analogues and from zero to 50.4 (median 2.8) for regular insulin. No study was designed to investigate possible long-term effects (e.g., mortality, diabetic complications), in particular in patients with diabetes-related complications.

Reviewers’ Conclusions. The authors conclude that their analysis suggests only a minor benefit of short-acting insulin analogues in the majority of patients with diabetes who are treated with insulin. Until long-term efficacy and safety data are available, the authors suggest a cautious response to the vigorous promotion of insulin analogues. Because of fears of potentially carcinogenic and proliferative effects, most studies to date have excluded patients with advanced diabetic complications. For safety purposes, we need a long-term follow-up of large numbers of patients who use short-acting insulin analogues. Furthermore, we need well-designed studies in pregnant women to determine the safety profile for the mother and the unborn child.

These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (www.cochrane.org).

In this Cochrane review,1 Siebenhofer and colleagues looked at regular insulin in comparison with short-acting analogues (lispro, aspart). Overall, they found that short-acting insulin analogues were as effective as regular human insulin in long-term glycemic control, and that they were similarly associated with episodes of hypoglycemia. The only difference found was in patients with type 1 diabetes, who had a small decrease in their A1C levels (about 0.1 percent; 0.2 percent in those who used continuous subcutaneous insulin infusions). It is unlikely that this difference is clinically significant. However, 10 percent of the included studies were only 28 days in duration, and 36 percent of the studies lasted fewer than 90 days. With intensive therapy, A1C levels can begin to drop in three to five weeks,5 but the full effect of a change in therapy may not occur until the end of the 120-day life span of the red blood cells. Thus, more than one third of the included studies may have had insufficient follow-up time to determine the full effect of the intervention on A1C levels.

No studies were found that compared regular insulin with short-acting analogues in terms of their effects on the long-term complications of diabetes. When the results from the Diabetes Control and Complications Trial Research Group study6 are extrapolated, a 0.1 percent reduction in A1C levels translates into a number needed to treat of 650 to prevent the development of diabetic retinopathy, and 765 to halt its progression.

Patients can achieve effective long-term control of blood sugar with regular insulin or a short-acting analogue. Regular and short-acting analogues are similar in achieving glycemic control in studies performed to date. Short-acting analogues may be advantageous in allowing for greater flexibility and convenience. For patients with type 1 diabetes, insulin analogues are slightly more effective than regular insulin, especially if the patient uses an insulin pump.

The Authors

MICHAEL SCHOOFF, M.D., is associate director of the Clarkson Family Medicine Residency Program in Omaha. He received his medical degree from the Uniformed Services University of the Health Sciences, F. Hébert School of Medicine, Bethesda, Md., and completed a family medicine residency at Womack Army Medical Center, Fort Bragg, N.C....

KRISTA EHLERS, M.D., is a third-year family medicine resident at the Clarkson Family Medicine Residency Program. She received her medical degree from the University of Nebraska College of Medicine in Omaha.

Address correspondence to Michael Schooff, M.D., Clarkson Family Medicine, 4200 Douglas St., Omaha, NE 68131 (e-mail:mschooff@nebraskamed.com). Reprints are not available from the authors.

6. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med.
1993;329:977–86.

The Cochrane Abstract is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Michael Schooff, M.D., and Krista Ehlers, M.D., present a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a full critique of the review.